The present invention relates generally to methods for the synthesis of optically pure 4-substituted-2-hydroxytetronic acid aci-reductone compounds.
The aci-reductone 4-(4-chlorophenyl)-2-hydroxytetronic acid compound (CHTA) of formula I ##STR1## is known to exhibit antilipidemic and antiaggregatory properties which differ from those of the classical phenoxyacetic acids as has been disclosed in Witiak et al., J. Med. Chem., 1988, 31, 1437-1445 and Kamanna et al., Lipids, 1989, 24, 25-32. Although, unsubstituted-, 2-alkyl- and 2-acyltetronic acids are frequently found in nature, Rao, Chem. Revs., 1976, 76, 625-694 and Pattenden, Fortschr. Chem. Org. Naturst., 1978, 35, 133-198; the 2-hydroxy substituted redox system, to our knowledge, is only found in vitamin C and the macrolide antibiotic chlorothricin, Berdy in "Handbook of Antibiotic Compounds", CRC, Boca Raton, FL., 1980, Vol. II, p. 415.
The antiaggregatory activites of 2-hydroxytetronic acid aci-reductone compound (CHTA) is of interest since blood platelets are involved in the genesis of atherosclerosis. 2-Hydroxytetronic acid aci-reductones inhibit collagen-induced human platelet aggregation and secretion of [.sup.14 C]-serotonin in a concentration-dependent manner at equivalent doses, as reported in Witiak et al., J. Med. Chem., 1982, 25, 90-93. The CHTA compound inhibits platelet function by a similar mechanism, involving arachidonic acid release. Redox analogues such as 2-hydroxytetronic acid function as antioxidants in membrances or interfere with free radical processes involved in the biosynthetic elaboration of cyclic prostaglandin endoperoxides (PGG.sub.2 and PGH.sub.2) and subsequently thromboxane A.sub.2 from arachidonic acid.
Synthesis of 4-substituted-2-hydroxytetronic acid compounds of the present invention is of formula II ##STR2## complicated by the stereochemical lability of the C-4 stereogenic center. The lability of this center in tetronic acids can be compared to the lability of the asymmetric center of mandelic acid; Whitesell et al., J. Org. Chem., 1983, 48, 3548-3551 and Gore et al., J. Org. Chem., 1986, 51, 3700-3704, and phenylglycine, Evans et al., Tetrahedron, 1988, 44, 5525-5540, Bodansky, "Principles of Peptide Syn.", Springer-Verlag, Berlin, N.Y., 1984, p. 160, which discloses that phenylglycine undergoes extensive racemization during peptide synthesis.
Older synthetic methods such as disclosed in Helferich et al., Ber., 1937, 70, 465-468, involving benzoin and intermolecular Claisen condensations employed in the synthesis of L-ascorbic acid, produce racemic 4-aryl-2-hydroxytetronic acids. Various syntheses published for the naturally occurring chiral tetronic acids such as (-)-vertinolide (Wrobel et al., J. Org. Chem., 1983, 48, 3761-3764); (S)-carlosic acid (Bloomer et al., J. Org. Chem., 1974, 39, 113-125); chlorothricin (Ireland et al. J. Org. Chem., 1986, 51, 635-648); related 2-acylated (Booth et al., J. Chem. Soc. Perkin Trans I, 1987, 121-129; or 2-unsubstituted (Brandange et al., J. Org. Chem., 1984, 49, 927-928) tetronic acids, and chiral tetronic acid intermediates useful for the synthesis of the seco acid of erthronolide B (Stork et al., J. Am. Chem. Soc., 1987, 109, 1564-1565), were not applicable for the synthesis of optically pure enantiomers of 4-aryl-2-hydroxytetronic acids. Some targets contain quaternary chiral centers not expected to undergo racemization during their preparation as disclosed in Wrobel et al., supra, and Ireland et al., supra.
Other syntheses are dependent upon intramolecular Claisen condensations facilitated by a second carbonyl function thereby affording 2-acyltetronic acids as disclosed in Bloomer et al., supra, and Booth, et al., supra. In some cases the 4-substituent at the chiral center is alkyl, as disclosed in Brandange et al., supra, and Stork, et al., supra, and therefore, racemization under reaction conditions employed is more easily prevented.
Thus, the literature contains no references to the preparation of optically pure stereogenically labile 4-substituted-2-hydroxytetronic acid compounds.